CN102231953A

CN102231953A - Organic compounds

Info

Publication number: CN102231953A
Application number: CN2009801480893A
Authority: CN
Inventors: P·李; L·P·文诺格勒
Original assignee: Intra Cellular Therapies Inc
Current assignee: Intra Cellular Therapies Inc
Priority date: 2008-12-06
Filing date: 2009-12-07
Publication date: 2011-11-02
Also published as: JP5778582B2; CO6390083A2; DOP2011000173A; MX2011005933A; KR20110095881A; CR20110312A; US20110245214A1; CL2011001263A1; US20140005155A1; JP2012510993A; EA201170770A1; AU2009322901A1; ECSP11011184A; CA2740391A1; BRPI0922348A2; IL213314A0; TN2011000246A1; US20150038474A1; EP2367429A1; PE20110922A1

Abstract

Optionally substituted 3-(thio, sulfonyl or sulfonyl)-7, 8-dihydro-(1H or 2H)- imidazo[1, 2-a]pyrazolo[4, 3-e]pyrimidin-4(5H)-one or a substituted 3-(thio, sulfinyl or sulfonyl)-7, 8, 9-trihydro- (1H or 2H)-pyrimido[1, 2-a]pyrazolo[4, 3-e]pyrimidin-4(5H)- one compounds or Compounds of Formula (I), processes for their production, their use as pharmaceuticals and pharmaceutical compositions comprising them.

Description

Organic compound

The application has required in the U.S. Provisional Application No.61/120 of submission on December 6th, 2008,442 priority, and the content whole of the document is incorporated herein by reference.

Technical field

The present invention relates to optional substituted 3-(sulfenyl, sulfinyl or sulfonyl)-7; 8-dihydro-(1H or 2H)-imidazo [1; 2-a] pyrazolo [4; 3-e] pyrimidine-4 (5H)-ketone or substituted 3-(sulfenyl, sulfinyl or sulfonyl)-7; 8; 9-three hydrogen-(1H or 2H)-pyrimido [1; 2-a] pyrazolo [4,3-e] pyrimidines-4 (5H)-ketonic compound, for example hereinafter described formula I compound, they the preparation method, they are as the purposes of medicine and comprise their pharmaceutical composition.Interested especially is to can be used as phosphodiesterase 1 (PDE1) inhibitor, for example can be used for treating infringement (for example in schizophrenia) or the obstacle that can be enhanced by the progesterone signal transduction path that strengthens such as the noval chemical compound of female sex dysfunction of the disease that relates to approach obstacle in the d1 dopamine receptor cell such as Parkinson's, depression, hypnolepsy, cognitive function.

Background of invention

Identified ten gang's phosphodiesterases (PDE), but only I family PDE, be Ca ²⁺-calmodulin-dependence phosphodiesterase (CaM-PDE) has been proved to be mediation calcium and cyclic nucleotide (for example cAMP and cGMP) signal transduction path.Three kinds of known CaM-PDE genes, be that PDE1A, PDE1B and PDE1C all express in central nervous system tissue.PDE1A expresses in whole brain, and the expression in the CA1 to CA3 of hippocampus layer and cerebellum is higher, and the expression in corpus straitum is low.PDE1A also expresses in lung and heart.PDE1B mainly expresses in corpus straitum, dentate fascia, tractus olfactorius and cerebellum, and it expresses relevant with the brain zone with high-level dopaminergic nerve distribution.Though PDE1B mainly expresses in central nervous system, it can be detected in heart.PDE1C mainly expresses in olfactory epithelium, cerebellar granule cell and corpus straitum.PDE1C also expresses in heart and vascular smooth muscle.

Cyclic nucleotide phosphodiesterase reduces cAMP and the conduction of cGMP signal in the cell by making these cyclic nucleotides be hydrolyzed to their non-activity 5 '-single phosphoric acid (5 ' AMP and 5 ' GMP) separately.CaM-PDE is in the mediation brain cell, particularly be called and play a crucial role aspect the signal transduction in the brain cell in basal nuclei or the striatal brain zone.For example, activation of NMDA-type glutamate receptor and/or d2 dopamine receptor activation cause intracellular calcium concentration to increase, thereby cause effector such as the activation of calmodulin-dependent kinases II (CaMKII) and calcineurin and the activation of CaM-PDE, cause cAMP and cGMP to reduce.On the other hand, the activation of d1 dopamine receptor activation causing nucleotide cyclase, thus cause cAMP and cGMP to increase.These cyclic nucleotides and then activated protein kinase A (PKA; The cAMP-deopendent protein kinase) and/or protein kinase G (PKG; The cGMP-deopendent protein kinase), described protein kinase phosphorylation downstream signal transduction pathway element such as DARPP-32 (phosphoprotein that dopamine and cAMP-regulate) and cAMP response element binding protein (CREB).The activity of the DARPP-32 of phosphorylation and then Profilin phosphatase-1 (PP-1), thus the phosphorylation state of increase substrate protein such as PgR (PR) causes inducing physiological reaction.Research in rodent has shown by the activation of dopamine D 1 or PgR induces the cAMP progesterone signal conduction relevant with various physiological reactions with the synthetic enhancing of cGMP, and described physiological reaction comprises lordosis reaction relevant with mating sensitivity in some rodents.Referring to people such as Mani, Science (2000) 287:1053, its content is incorporated herein by reference.

Therefore, CaM-PDE can influence dopamine modulating in the basal nuclei (corpus straitum) with other cell in signal transduction path, include but not limited to signal transduction path in nitrogen oxide, norepinephrine energy, neurotensin, CCK, VIP, thrombocytin, glutamic acid (for example nmda receptor, ampa receptor), GABA, acetylcholine, adenosine (for example A2A acceptor), Cannabined receptor, natriuretic peptide (for example ANP, BNP, CNP), DARPP-32 and the endorphin cell.

Phosphodiesterase (PDE) is active, particularly phosphodiesterase 1 (PDE1) activity conditioning agent as motor activity and learning and memory in brain tissue works.PDE1 is a treatment target spot of regulating signal transduction path in the cell, preferably in nervous system, include but not limited to signal transduction path and progesterone signal transduction path in d1 dopamine receptor, d2 dopamine receptor, nitrogen oxide, norepinephrine energy, neurotensin, CCK, VIP, thrombocytin, glutamic acid (for example nmda receptor, ampa receptor), GABA, acetylcholine, adenosine (for example A2A acceptor), Cannabined receptor, natriuretic peptide (for example ANP, BNP, CNP), the endorphin cell.For example, PDE1B suppresses to avoid degrading by protection cGMP and cAMP to strengthen the effect of dopamine D 1 activator, and should suppress the d2 dopamine receptor signal transduction path similarly by suppressing the PDE1 activity.The long-term rising of intracellular Ca2+ level is relevant with the cell death in the various diseases, particularly with neurodegenerative disease such as Alzheimer disease, Parkinson's and Huntington and cause apoplexy and the circulatory system obstacle of miocardial infarction in cell death relevant.Therefore, the PDE1 inhibitor has potential to can be used for being reduced to the d1 dopamine receptor signaling activity disease of feature, as Parkinson's, restless legs syndrome, depression, hypnolepsy and Cognitive function damage (cognitive impairment).The PDE1 inhibitor also can be used for the disease such as the female sex dysfunction that can be alleviated by strengthening the conduction of progesterone signal.

The compound that therefore, need optionally suppress PDE1 activity, especially PDE1A or PDE1B activity.

Summary of the invention

The invention provides the optional substituted 3-(sulfenyl, sulfinyl or sulfonyl)-7 of free form or salt form; 8-dihydro-(1H or 2H)-imidazo [1; 2-a] pyrazolo [4; 3-e] pyrimidine-4 (5H)-ketone or substituted 3-(sulfenyl, sulfinyl or sulfonyl)-7; 8; described compound, for example formula II compound of 9-three hydrogen-(1H or 2H)-pyrimido [1,2-a] pyrazolo [4,3-e] pyrimidines-4 (5H)-ketone, for example (1 or 2 and/or 5)-replacement:

Formula II

Wherein

(i) L is S, SO or SO ₂

(ii) R ₁Be H or C _1-4Alkyl (for example methyl or ethyl);

(iii) R ₄Be H or C _1-6Alkyl (for example methyl, isopropyl), and R ₂And R ₃Be H or optional independently by the C of halogen or hydroxyl replacement _1-6Alkyl (for example methyl or isopropyl) (R for example ₂And R ₃All be methyl, perhaps R ₂Be H and R ₃Be methyl, ethyl, isopropyl or hydroxyethyl), aryl, heteroaryl, (optional assorted) alkoxy aryl, (optional assorted) aryl C _1-6Alkyl, perhaps R ₂And R ₃Form 3-to 6-unit ring together;

Perhaps

R ₂Be H and R ₃And R ₄Form two together-, three-or four-methylene bridge,

(preferred R wherein ₃And R ₄Have cis-configuration together, for example wherein have R ₃And R ₄Carbon have R and S configuration respectively);

(iv)R ₅

A) be-D-E-F, wherein:

D is C _1-4Alkylidene (for example methylene, ethylidene or third-2-alkynes-1-subunit);

E is singly-bound, C _2-4Alkynylene (for example-C ≡ C-), arlydene (for example phenylene) or inferior heteroaryl (for example inferior pyridine radicals);

F is

H，

Aryl (for example phenyl),

Heteroaryl (for example pyridine radicals, di azoly, triazolyl, as pyridine-2-base, imidazoles-1-base, 1,2,4-triazol-1-yl),

Halogen (for example F, Br, Cl),

Halo C _1-4Alkyl (for example trifluoromethyl),

-C(O)-R ₁₅，

-N(R ₁₆)(R ₁₇)，

-S (O) ₂R ₂₁, or

Choose wantonly and contain the C that at least one is selected from the atom of N or O _3-7Cycloalkyl (for example cyclopenta, cyclohexyl, pyrrolidinyl (for example pyrrolidines-3-yl), tetrahydrochysene-2H-pyrans-4-base or morpholinyl);

Wherein D, E and F are replaced by one or more following groups independently and randomly:

Halogen (for example F, Cl or Br),

C _1-4Alkyl (for example methyl),

Halo C _1-4Alkyl (for example trifluoromethyl),

For example, F is a heteroaryl, pyridine radicals for example, it is replaced by one or more following groups: halogen (for example 6-fluorine pyridine-2-base, 5-fluorine pyridine-2-base, 6-fluorine pyridine-2-base, 3-fluorine pyridine-2-base, 4-fluorine pyridine-2-base, 4,6-dichloropyridine-2-yl), halo C _1-4Alkyl (for example 5-5-flumethiazine-2-yl) or C _1-4Alkyl (for example 5-picoline-2-yl), perhaps F is an aryl, phenyl for example, it is replaced (for example 4-fluorophenyl) by one or more halogens, and perhaps F is C _3-7Heterocyclylalkyl (for example pyrrolidinyl), it is optional by C _1-6Alkyl replaces (for example 1-methylpyrrolidin-3-yl); Perhaps

B) be substituted heteroaryl alkyl, for example replaced by haloalkyl;

C) be connected with one of nitrogen on the pyrazolo of the formula I part, and be the group of formula A:

Formula A

Wherein X, Y and Z are N or C independently, R ₈, R ₉, R ₁₁And R ₁₂Be H or halogen (for example Cl or F) independently, and R ₁₀Be

Halogen,

C _1-4Alkyl,

C _3-7Cycloalkyl,

Assorted C _3-7Cycloalkyl (for example pyrrolidinyl or piperidyl),

C _1-4Haloalkyl (for example trifluoromethyl),

Aryl (for example phenyl),

Heteroaryl (for example pyridine radicals (for example pyridine-2-yl) or thiadiazolyl group (for example 1,2,3-thiadiazoles-4-yl)), di azoly, triazolyl, tetrazole radical,

Aryl carbonyl (for example benzoyl),

Alkyl sulphonyl (for example methyl sulphonyl),

The heteroaryl carbonyl, or

Alkoxy carbonyl,

Wherein said aryl, heteroaryl, cycloalkyl or Heterocyclylalkyl are optional by one or more halogens (for example F or Cl), C _1-4Alkyl, C _1-4Alkoxyl, C _1-4Haloalkyl (for example trifluoromethyl) and/or-SH replaces,

Preferred R ₁₀Be phenyl, pyridine radicals, piperidyl or pyrrolidinyl, it is optional by the defined substituting group replacement in front, and is for example optional by halogen or alkyl replacement;

Condition is when X, Y or Z are nitrogen, R ₈, R ₉Or R ₁₀Do not exist respectively;

(v) R ₆Be

H，

C _1-4Alkyl (for example methyl),

C _3-7Cycloalkyl (for example cyclopenta),

Aryl (for example phenyl),

Heteroaryl (for example pyridine radicals, as pyridin-4-yl),

Aryl C _1-4Alkyl (for example benzyl),

Arylamino (for example phenyl amino),

Heteroaryl amino,

N, N-two C _1-4Alkyl amino,

N, the N-ammonia diaryl base,

N-aryl-N-(aryl C _1-4Alkyl) amino (for example N-phenyl-N-(1,1 '-biphenyl-4-ylmethyl) amino), or

-N(R ₁₈)(R ₁₉)；

Wherein aryl or heteroaryl are optional by one or more halogens (for example F, Cl), hydroxyl or C _1-6Alkoxyl (for example methoxyl group) replaces, for example, and R ₆Be 4-hydroxy phenyl or 4-fluorophenyl,

(vi) n=0 or 1;

(vii) when n=1, A is-C (R ₁₃R ₁₄)-, be R wherein ₁₃And R ₁₄Be H or C independently _1-4Alkyl, aryl, heteroaryl, (optional assorted) aryl C _1-4Alkoxyl or (optional assorted) aryl C _1-4Alkyl, perhaps R ₁₃Or R ₁₄Can with R ₂Or R ₄Form bridge;

(viii) R ₁₅Be C _1-4Alkyl, halo C _1-4Alkyl ,-OH or-OC _1-4Alkyl (for example-OCH ₃);

(ix) R ₁₆And R ₁₇Be H or C independently _1-4Alkyl;

(x) R ₁₈And R ₁₉Be H, C independently _1-4Alkyl, C _3-8Cycloalkyl, assorted C _3-8Cycloalkyl, aryl (for example phenyl) or heteroaryl, wherein said aryl or heteroaryl are optional by one or more following groups replacements: halogen (fluorophenyl for example, as the 4-fluorophenyl), hydroxyl (for example hydroxy phenyl, as 4-hydroxy phenyl or 2-hydroxy phenyl), C _1-6Alkyl, halo C _1-6Alkyl, C _1-6Alkoxyl, aryl, heteroaryl or C _3-8Cycloalkyl,

(xi) R ₂₀Be H, C _1-4Alkyl (for example methyl) or C _3-7Cycloalkyl,

(xii) R ₂₁Be C _1-6Alkyl.

In another embodiment, the invention provides the formula I compound of free form or salt form:

Formula I

Wherein

(i) L is S, SO or SO ₂

(ii) R ₁Be H or C _1-4Alkyl (for example methyl or ethyl);

(iii) R ₄Be H or C _1-6Alkyl (for example methyl, isopropyl), and R ₂And R ₃Be H or optional independently by the C of halogen or hydroxyl replacement _1-6Alkyl (for example methyl or isopropyl) (R for example ₂And R ₃All be methyl, perhaps R ₂Be H and R ₃Be methyl, ethyl, isopropyl or hydroxyethyl), aryl, heteroaryl, (optional assorted) alkoxy aryl or (optional assorted) aryl C _1-6Alkyl;

Perhaps

R ₂Be H, and R ₃And R ₄Form two together-, three-or four-methylene bridge,

(iv)R ₅

A) be-D-E-F, wherein:

F is

H，

Aryl (for example phenyl),

Halogen (for example F, Br, Cl),

Halo C _1-4Alkyl (for example trifluoromethyl),

-C(O)-R ₁₅，

-N(R ₁₆)(R ₁₇)，

-S (O) ₂R ₂₁, or

Halogen (for example F, Cl or Br),

C _1-4Alkyl (for example methyl),

Halo C _1-4Alkyl (for example trifluoromethyl),

B) be substituted heteroaryl alkyl, for example replaced by haloalkyl;

Formula A

Wherein X, Y and Z are N or C independently, R ₈, R ₉, R ₁₁And R ₁₂Be H or halogen (for example Cl or F) independently, and R ₁₀Be halogen, C _1-4Alkyl, C _3-7Cycloalkyl, C _1-4(for example pyridine radicals (for example pyridine-2-yl) or thiadiazolyl group (for example 1 for haloalkyl (for example trifluoromethyl), aryl (for example phenyl), heteroaryl, 2,3-thiadiazoles-4-yl)), di azoly, triazolyl, tetrazole radical, aryl carbonyl (for example benzoyl), alkyl sulphonyl (for example methyl sulphonyl), heteroaryl carbonyl or alkoxy carbonyl; Condition is when X, Y or Z are nitrogen, R ₈, R ₉Or R ₁₀Do not exist respectively;

(v) R ₆Be

H，

C _1-4Alkyl (for example methyl),

C _3-7Cycloalkyl (for example cyclopenta),

Aryl (for example phenyl),

Heteroaryl (for example pyridine radicals, as pyridin-4-yl),

Aryl C _1-4Alkyl (for example benzyl),

Arylamino (for example phenyl amino),

Heteroaryl amino,

N, N-two C _1-4Alkyl amino,

N, the N-ammonia diaryl base,

-N(R ₁₈)(R ₁₉)；

(vi) n=0 or 1;

(vii) when n=1, A is-C (R ₁₃R ₁₄)-, be R wherein ₁₃And R ₁₄Be H or C independently _1-4Alkyl, aryl, heteroaryl, (optional assorted) aryl C _1-4Alkoxyl or (optional assorted) aryl C _1-4Alkyl;

(ix) R ₁₆And R ₁₇Be H or C independently _1-4Alkyl;

(x) R ₁₈And R ₁₉Be H, C independently _1-4Alkyl or aryl (for example phenyl), wherein said aryl is optional by one or more following groups replacements: halogen (for example fluorophenyl, as the 4-fluorophenyl) or hydroxyl (for example hydroxy phenyl, for example 4-hydroxy phenyl or 2-hydroxy phenyl);

(xi) R ₂₀Be H, C _1-4Alkyl (for example methyl) or C _3-7Cycloalkyl,

(xii) R ₂₁Be C _1-6Alkyl.

The present invention also provide free form or salt form as shown in the formula the I compound:

1.1 formula I, wherein L is S, SO or SO ₂

1.2 formula I or 1.1, wherein L is S;

1.3 formula I or 1.1, wherein L is-SO-;

1.4 formula I or 1.1, wherein L is-SO ₂-;

1.5 among formula I or the 1.1-1.4 any one, R wherein ₁Be H or C _1-4Alkyl (for example methyl);

1.6 formula 1.5, wherein R ₁Be H;

1.7 formula 1.5, wherein R ₁Be C _1-4Alkyl (for example methyl or ethyl);

1.8 among formula I or the 1.1-1.7 any one, R wherein ₄Be H or C _1-6Alkyl (for example methyl, isopropyl) and R ₂And R ₃Be H or optional independently by the C of halogen or hydroxyl replacement _1-6Alkyl (for example methyl or isopropyl) (R for example ₂And R ₃All be methyl, perhaps R ₂Be H and R ₃Be methyl, ethyl, isopropyl or hydroxyethyl), aryl, heteroaryl, (optional assorted) alkoxy aryl or (optional assorted) aryl C _1-6Alkyl;

1.9 formula 1.8, wherein R ₂Or R ₃Be H or C _1-6Alkyl (for example methyl or isopropyl);

1.10 formula 1.8, wherein R ₂Or R ₃Be H;

1.11 formula 1.8, wherein R ₂Or R ₃Be C _1-6Alkyl (for example methyl or isopropyl);

1.12 formula 1.8, wherein R ₂Or R ₃It is methyl;

1.13 formula 1.8, wherein R ₂Or R ₃It is isopropyl;

1.14 among formula I or the 1.1-1.7 any one, R wherein ₂Be H and R ₃And R ₄Form two together-, three-or four-methylene bridge (preferred R wherein ₃And R ₄Have cis-configuration together, for example wherein have R ₃And R ₄Carbon have R and S configuration respectively);

1.15 among formula I or the 1.1-1.14 any one, R wherein ₅Be-D-E-F;

1.16 formula 1.15, wherein D is C _1-4Alkylidene (for example methylene, ethylidene or third-2-alkynes-1-subunit);

1.17 formula 1.16, wherein D is a methylene;

1.181.15-1.17 in any one, wherein E is singly-bound, C _2-4Alkynylene (for example-C ≡ C-), arlydene (for example phenylene) or inferior heteroaryl (for example inferior pyridine radicals);

1.19 among the formula 1.15-1.17 any one, wherein E is arlydene (a for example phenylene);

1.20 among the formula 1.15-1.17 any one, wherein E is a phenylene;

1.21 among the formula 1.15-1.17 any one, wherein E is inferior heteroaryl (a for example inferior pyridine radicals);

1.22 among the formula 1.15-1.17 any one, wherein E is a phenylene, wherein F is that contraposition replaces;

1.23 among the formula 1.15-1.17 any one, wherein E is inferior heteroaryl (a for example inferior pyridine radicals);

1.24 among the formula 1.15-1.17 any one, wherein E is a singly-bound;

1.25 among the formula 1.15-1.24 any one, wherein F is H, aryl (for example phenyl), heteroaryl (for example pyridine radicals, di azoly, triazolyl, as pyridine-2-base, imidazoles-1-base, 1,2,4-triazol-1-yl), halogen (for example F, Br, Cl), halo C _1-4Alkyl (for example trifluoromethyl) ,-C (O)-R ₁₅,-N (R ₁₆) (R ₁₇) ,-S (O) ₂R ₂₁Or optional contain the C that at least one is selected from the atom of N or O _3-7Cycloalkyl (for example cyclopenta, cyclohexyl, pyrrolidinyl (for example pyrrolidines-3-yl), tetrahydrochysene-2H-pyrans-4-base or morpholinyl);

1.26 formula 1.25, wherein F is halo C _1-4Alkyl (for example trifluoromethyl);

1.27 formula 1.25, wherein F is a trifluoromethyl;

1.28 formula 1.25, wherein F is halogen (for example F, Br, Cl);

1.29 formula 1.25, wherein F is Cl;

1.30 formula 1.25, wherein F is heteroaryl (for example pyridine radicals, as pyridine-2-yl);

1.31 formula 1.25, wherein F is a pyridine radicals;

1.32 formula 1.25, wherein F is pyridine-2-base;

1.33 formula 1.25, wherein F is the optional C that at least one is selected from the atom of N or O that contains _3-7Cycloalkyl (for example cyclopenta, cyclohexyl, pyrrolidinyl (for example pyrrolidines-3-yl), tetrahydrochysene-2H-pyrans-4-base, morpholinyl);

1.34 formula 1.25, wherein F is a cyclohexyl;

1.35 formula 1.25, wherein F is pyrrolidinyl (for example pyrrolidines-3-yl);

1.36 formula 1.25, wherein F is a cyclopenta;

1.37 formula 1.25, wherein F is tetrahydrochysene-2H-pyrans-4-base;

1.38 formula 1.25, wherein F is aryl (a for example phenyl);

1.39 formula 1.25, wherein F is a phenyl;

1.40 formula 1.25, wherein F is the 4-chlorphenyl;

1.41 formula 1.25, wherein F is-S (O) ₂R ₂₁, R wherein ₂₁Be C _1-6Alkyl (for example methyl);

1.42 formula 1.25, wherein F is-C (O)-R ₁₅And R ₁₅Be C _1-4Alkyl (for example methyl), halo C _1-4Alkyl (for example trifluoromethyl) ,-OH or-OC _1-4Alkyl (for example-OCH ₃);

1.43 among the formula 1.15-1.42 any one, wherein D, E and F are independently with randomly by one or more halogens (for example F, Cl or Br), C _1-4Alkyl (for example methyl), halo C _1-4Alkyl (for example trifluoromethyl) replaces, for example F is a heteroaryl, pyridine radicals for example, it is replaced by one or more following groups: halogen (for example 6-fluorine pyridine-2-base, 5-fluorine pyridine-2-base, 6-fluorine pyridine-2-base, 3-fluorine pyridine-2-base, 4-fluorine pyridine-2-base, 4,6-dichloropyridine-2-yl), halo C _1-4Alkyl (for example 5-5-flumethiazine-2-yl) or C _1-4Alkyl (for example 5-picoline-2-yl), perhaps F is an aryl, phenyl for example, it is replaced (for example 4-fluorophenyl) by one or more halogens, or F is C _3-7Heterocyclylalkyl (for example pyrrolidinyl), it is optional by C _1-6Alkyl replaces (for example 1-methylpyrrolidin-3-yl);

1.44 formula 1.43, wherein F is by one or more halogens (for example F, Cl or Br), C _1-4Alkyl (for example methyl), halo C _1-4Alkyl (for example trifluoromethyl) replaces;

1.45 formula 1.43, wherein F is 6-fluorine pyridine-2-base;

1.46 formula 1.43, wherein F is 3-fluorine pyridine-2-base;

1.47 formula 1.43, wherein F is 4-fluorine pyridine-2-base;

1.48 formula 1.43, wherein F is 5-fluorine pyridine-2-base;

1.49 formula 1.43, wherein F is a heteroaryl, pyridine radicals for example, and it is optional by one or more halo C _1-4Alkyl replaces (for example 5-5-flumethiazine-2-yl);

1.50 formula 1.43, wherein F is 5-5-flumethiazine-2-base;

1.51 formula 1.43, wherein F is a heteroaryl, pyridine radicals for example, and it is optional by one or more C _1-4Alkyl replaces (for example 5-picoline-2-yl);

1.52 formula 1.43, wherein F is 5-picoline-2-base;

1.53 formula 1.25, wherein F is-C (O)-R ₁₅And R ₁₅It is methyl;

1.54 formula 1.25, wherein F is-C (O)-R ₁₅And R ₁₅It is trifluoromethyl;

1.55 formula 1.25, wherein F is-C (O)-R ₁₅And R ₁₅Be-OH;

1.56 formula 1.25, wherein F is-C (O)-R ₁₅And R ₁₅Be-OC _1-4Alkyl (for example-OCH ₃);

1.57 formula 1.25, wherein F is-C (O)-R ₁₅And R ₁₅Be-OCH ₃

1.58 formula 1.25, wherein F is-N (R ₁₆) (R ₁₇);

1.59 among formula I or the 1.1-1.14 any one, R wherein ₅Be substituted heteroaryl alkyl, for example replaced by haloalkyl;

1.60 among formula I or the 1.1-1.14 any one, R wherein ₅Be connected with one of nitrogen on the pyrazolo of the formula I part, and be the group of formula A:

Formula A

1.61 formula 1.60, wherein R ₅Be substituted heteroaryl methyl, for example replaced by the haloalkyl contraposition;

1.62 formula 1.60, wherein R ₅Be the group of formula A, wherein R ₈, R ₉, R ₁₁And R ₁₂Be H and R ₁₀It is phenyl;

1.63 formula 1.60, wherein R ₅Be the group of formula A, wherein R ₈, R ₉, R ₁₁And R ₁₂Be H and R ₁₀Be pyridine radicals or thiadiazolyl group;

1.64 formula 1.60, wherein R ₅Be the group of formula A, wherein R ₈, R ₉, R ₁₁And R ₁₂Be H or halogen independently, and R ₁₀It is haloalkyl;

1.65 formula 1.60, wherein R ₅Be the group of formula A, wherein R ₈, R ₉, R ₁₁And R ₁₂Be H independently, and R ₁₀It is alkyl sulphonyl;

1.66 among formula I or the 1.1-1.65 any one, R wherein ₆Be H, C _1-4Alkyl (for example methyl), C _3-7Cycloalkyl (for example cyclopenta), aryl, heteroaryl, aryl C _1-4Alkyl (for example benzyl), arylamino (for example phenyl amino), heteroaryl amino, N, N-two C _1-4Alkyl amino, N, N-ammonia diaryl base, N-aryl-N-(aryl C _1-4Alkyl) amino (for example N-phenyl-N-(1,1 '-biphenyl-4-ylmethyl) amino) or-N (R ₁₈) (R ₁₉), wherein aryl or heteroaryl are optional by one or more halogens (for example F, Cl), hydroxyl or C _1-6Alkoxyl (for example methoxyl group) replaces;

1.67 formula 1.66, wherein R ₆Be H;

1.68 formula 1.66, wherein R ₆Be C _1-4Alkyl (for example methyl);

1.69 formula 1.66, wherein R ₆Be C _3-7Cycloalkyl (for example cyclopenta);

1.70 formula 1.66, wherein R ₆Be aryl (for example phenyl), it is optional by one or more halogens (for example F, Cl), hydroxyl or C _1-6Alkoxyl (for example methoxyl group) replaces;

1.71 formula 1.66, wherein R ₆Be fluorophenyl (for example 4-fluorophenyl) or hydroxy phenyl (for example 4-hydroxy phenyl);

1.72 among formula I or the 1.1-1.71 any one, n=0 wherein;

1.73 among formula I or the 1.1-1.71 any one, n=1 wherein;

1.74 formula 1.73, n=1 wherein, A is-C (R ₁₃R ₁₄)-, be R wherein ₁₃And R ₁₄Be H or C independently _1-4Alkyl, aryl, heteroaryl, (optional assorted) aryl C _1-4Alkoxyl or (optional assorted) aryl C _1-4Alkyl;

1.75 any one in the aforementioned formula, wherein said compound is selected from:

1.76 any one in the aforementioned formula, wherein said compound suppresses phosphodiesterase mediation (for example PDE1-mediation, especially PDE1B-mediation) cGMP hydrolysis, for example its IC in the affine particulate reagent of fixing metal PDE determination method, in example this determination method as described in example 9 above ₅₀Less than 1 μ M, preferably less than 500nM, be more preferably less than 50nM.

In another embodiment, the invention provides formula I or II compound, the wherein R of free form or salt form ₆Be:

H，

C _1-4Alkyl (for example methyl),

C _3-7Cycloalkyl (for example cyclopenta),

Aryl (for example phenyl),

Heteroaryl (for example pyridine radicals, as pyridin-4-yl),

Aryl C _1-4Alkyl (for example benzyl),

And remaining substituting group as the front in formula I or II or 1.1-1.76 in any one definition.

In another embodiment, the invention provides the formula I or the II compound of free form or salt form, wherein:

R ₅Be connected with one of nitrogen on the pyrazolo of formula I or the II part, and be the group of formula A:

Formula A

Halogen,

C _1-4Alkyl,

C _3-7Cycloalkyl,

Heterocyclylalkyl (for example pyrrolidinyl or piperidyl),

C _1-4Haloalkyl (for example trifluoromethyl),

Aryl (for example phenyl),

Aryl carbonyl (for example benzoyl),

Alkyl sulphonyl (for example methyl sulphonyl),

The heteroaryl carbonyl, or

Alkoxy carbonyl,

R ₆Be:

H，

C _1-4Alkyl (for example methyl),

C _3-7Cycloalkyl (for example cyclopenta),

Aryl (for example phenyl),

Heteroaryl (for example pyridine radicals, as pyridin-4-yl),

Aryl C _1-4Alkyl (for example benzyl),

Formula A

Halogen,

C _1-4Alkyl,

C _3-7Cycloalkyl,

Heterocyclylalkyl (for example pyrrolidinyl or piperidyl),

C _1-4Haloalkyl (for example trifluoromethyl),

Aryl (for example phenyl),

Aryl carbonyl (for example benzoyl),

Alkyl sulphonyl (for example methyl sulphonyl),

The heteroaryl carbonyl, or

Alkoxy carbonyl,

R ₆Be:

H，

C _1-4Alkyl (for example methyl),

Aryl (for example phenyl),

Heteroaryl (for example pyridine radicals, as pyridin-4-yl),

Formula A

Heterocyclylalkyl (for example pyrrolidinyl or piperidyl),

Aryl (for example phenyl),

Wherein said aryl, heteroaryl or Heterocyclylalkyl are optional by one or more halogens (for example F or Cl), C _1-4Alkyl, C _1-4Alkoxyl, C _1-4Haloalkyl (for example trifluoromethyl) and/or-SH replaces,

R ₆Be:

H，

C _1-4Alkyl (for example methyl),

Aryl (for example phenyl),

Heteroaryl (for example pyridine radicals, as pyridin-4-yl),

If context does not specify or can't determine that the following term of this paper has following implication from context is clear:

(a) " alkyl " used herein is saturated or undersaturated alkyl, preferably saturated, preferably has 1 to 6 carbon atom, its can be straight chain or side chain, and can choose wantonly coverlet-, two-or three-replace, for example by halogen (for example chlorine or fluorine), hydroxyl or carboxyl list-, two-or three-replace.

(b) " cycloalkyl " used herein is saturated or undersaturated non-aromatic hydrocarbyl, preferably saturated, preferably comprise 3 to 9 carbon atoms, wherein at least some carbon atoms form non-aromatic monocyclic or two ring or bridged ring structures, it can be chosen wantonly and be substituted, for example by halogen (for example chlorine or fluorine), hydroxyl or carboxyl substituted.Wherein cycloalkyl is chosen the atom that contains one or more N of being selected from and O and/or S wantonly, and described cycloalkyl can also be a Heterocyclylalkyl.

(c) except as otherwise noted, otherwise " Heterocyclylalkyl " is saturated or undersaturated non-aromatic hydrocarbyl, preferably saturated, preferably comprise 3 to 9 carbon atoms, wherein at least some carbon atoms form non-aromatic monocyclic or two ring or bridged ring structures, wherein at least one carbon atom is replaced by N, O or S, and described Heterocyclylalkyl can be chosen wantonly and be substituted, for example by halogen (for example chlorine or fluorine), hydroxyl or carboxyl substituted.

(d) " aryl " used herein is monocycle or bicyclic aromatic hydrocarbon, phenyl preferably, its optional being substituted is for example replaced (for example xenyl or pyridine radicals phenyl) by alkyl (for example methyl), halogen (for example chlorine or fluorine), haloalkyl (for example trifluoromethyl), hydroxyl, carboxyl or other aryl or heteroaryl.

(e) " heteroaryl " used herein is that wherein to constitute one or more in the atom of aromatic ring be sulphur or nitrogen but not the aromatic group of carbon, for example pyridine radicals or thiadiazolyl group, it can be chosen wantonly and be substituted, for example by alkyl, halogen, haloalkyl, hydroxyl or carboxyl substituted.

(f) when E is phenylene, number as follows:

(g) when substituting group with " Asia " beginning or when ending up with " subunit ", for example alkylidene, phenylene or Asia (aryl alkyl), described substituting group is with two other substituting group bridge joints or be connected.Therefore, methylene is-CH ₂-, phenylene is-C ₆H ₄-, inferior (aryl alkyl) is-C ₆H ₄-CH ₂-or-CH ₂-C ₆H ₄-.

Compound of the present invention, for example substituted 4; 5; 7; 8-tetrahydrochysene-(1H or 2H)-imidazo [1,2-a] pyrazolo [4,3-e] pyrimidine or substituted 3-(sulfenyl, sulfinyl or sulfonyl)-7; 8; among 9-three hydrogen-(1H or 2H)-pyrimido [1,2-a] pyrazolo [4,3-e] pyrimidines-4 (5H)-ketonic compound, for example formula I compound, for example formula 1.1-1.76 compound of any one can be with free form or salt form, for example exist with the acid-addition salts form.In this manual, except as otherwise noted, otherwise should be understood to comprise the compound of arbitrary form, for example free form or acid-addition salts form such as statements such as " compounds of the present invention ", perhaps contain under the acid substituent situation, also comprise the base addition salts form at compound.Compound of the present invention is intended to as medicine, thereby pharmaceutically acceptable salt is preferred.The salt that is unsuitable for medicinal usage can be used for for example free compound of the present invention or its pharmaceutically acceptable salt of isolated or purified, therefore is also included within " compound of the present invention ".

Compound of the present invention can also exist with prodrug forms in some cases.Prodrug forms is the compound that is converted into compound of the present invention in vivo.For example, when compound of the present invention contained hydroxyl or carboxyl substituent, these substituting groups can form hydrolyzable and acceptable ester on the physiology." hydrolyzable and acceptable ester on the physiology " used herein means under physiological condition the ester that can hydrolysis generates the compound of the present invention of acid (having at compound of the present invention under the situation of hydroxyl substituent) or alcohol (having at compound of the present invention under the situation of carboxyl substituent), and they are from being can tolerate on the physiology under dosage to be administered.Therefore, (compound-OH) for example, is compound-O-C (O)-C at the acyl ester prodrug of this compound when compound of the present invention contains hydroxyl _1-4Alkyl is hydrolysis in vivo, and (compound-OH) forms acid (HOC (O)-C for example on the other hand to form on the one hand hydrolyzable alcohol on the physiology _1-4Alkyl).Perhaps, when compound of the present invention contains carboxylic acid (for example compound-C (O) OH), the acid esters prodrug of this compound, be compound-C (O) O-C _1-4Alkyl can hydrolysis form compound-C (O) OH and HO-C _1-4Alkyl.Therefore, such just as will be appreciated, this term comprises conventional medicinal prodrug forms.

The present invention also provides the method for preparing compound of the present invention and has used disease that compounds for treating of the present invention hereinafter provides and obstacle (is especially treated with the d1 dopamine receptor signaling activity of reduction disease such as the Parkinson's as feature, tourette's syndrome, autism, fragile X syndrome, ADHD, restless legs syndrome, depressed, schizoid Cognitive function damage, hypnolepsy and the disease such as the female sex dysfunction that can be alleviated by strengthening the conduction of progesterone signal) or such as disease or obstacles such as mental disease or glaucomas) method.This tabulation is not an exhaustive, can comprise hereinafter given other disease and obstacle.

In another embodiment, the present invention also provides pharmaceutical composition, the pharmaceutically acceptable carrier that it comprises the compound of the present invention of free form, pharmaceutically acceptable salt form or prodrug forms and mixes with it.

Detailed Description Of The Invention

The method for preparing compound of the present invention

The pharmaceutically acceptable salt of compound of the present invention and they can adopt described herein and the method for being given an example and by similar method and prepare by the known method of chemical field with it.These class methods include but not limited to hereinafter described those.If can not obtain by commercial sources, the raw material that then is used for these methods can adopt by the operation that is selected from chemical field and be similar to or prepare similar in appearance to the synthetic technology of known compound.Various raw materials and/or compound of the present invention can adopt the method preparation described in WO 2006/133261 and the PCT/US2007/070551.The equal integral body of all lists of references that this paper quotes is incorporated herein by reference.

Compound of the present invention comprises their enantiomter, diastereoisomer and racemate and their polymorph, hydrate, solvate and compound.The individual compound of within the scope of the invention some can contain two keys.The description of two keys in the present invention means E and the Z isomer that comprises two keys.In addition, some compounds in the scope of the invention may contain one or more asymmetric centers.The present invention includes the use of any combination of any optically-active pure stereoisomers and stereoisomer.

Compound of the present invention is also contained their stable and unsettled isotope.Stable isotope is to compare the non radioactive isotope that contains an other neutron with the nucleic that enriches of identical type (being element).The activity that expection comprises the isotopic compound of this class will be retained, and this compounds also will have the function of the pharmacokinetics that is used to measure the heterotope analog.For example, the locational hydrogen atom of certain of compound of the present invention can be replaced by deuterium (a kind of inactive stable isotope).The example of known stable isotope include but not limited to deuterium, ¹³C, ¹⁵N, ¹⁸O.Perhaps, with identical type (being element) enrich nucleic compare contain other neutron and be radioactive unsettled isotope for example ¹²³I, ¹³¹I, ¹²⁵I, ¹¹C, ¹⁸F can substitute I, the corresponding rich variety of C and F.Useful isotopic another example of compound of the present invention is ¹¹The C isotope.These radioisotope can be used for the Study on pharmacokinetics of radiophotography and/or compound of the present invention.

Fusing point is not calibrated, and (dec) expression is decomposed.Temperature with degree centigrade (℃) provide; Except as otherwise noted, otherwise operate under room temperature or the environmental temperature, promptly carry out under the temperature in 18-25 ℃ of scope.Chromatography means sudden strain of a muscle formula silica gel chromatography; Thin-layer chromatography (TLC) is carried out on silica gel plate.The NMR data are δ values of principal character (diagnostic) proton, to provide with respect to the PPM (ppm) as interior target tetramethylsilane (TMS).Use is used for the routine abbreviation of signal shape.Coupling constant (J) provides with Hz.For mass spectrometry (MS), the minimum quality leading ion of reporter molecule, wherein isotopic spliting causes multiple mass spectra peak.The solvent mixture composition provides with percent by volume or volume ratio.Under NMR spectrum complicated situation, only report characteristic signal.

Term and abbreviation:

The BuLi=n-BuLi

Bu ^tThe OH=tert-butyl alcohol

CAN=cerous nitrate (IV) ammonium

The DIPEA=diisopropyl ethyl amine

DMF=N, dinethylformamide

The DMSO=dimethyl sulfoxide (DMSO)

Et ₂The O=ether

EtOAc=ethyl acetate

The equiv.=equivalent

H=hour

The HPLC=high performance liquid chromatography

The LDA=lithium diisopropylamine

MeOH=methyl alcohol

The NBS=N-bromo-succinimide

The NCS=N-chlorosuccinimide

NaHCO ₃=sodium bicarbonate

NH ₄OH=ammonium hydroxide

Pd ₂(dba) ₃=three [dibenzalacetones] two palladiums (0)

PMB=is to methoxy-benzyl

POCl ₃=phosphorous oxychloride

SOCl ₂=thionyl chloride

The TFA=trifluoroacetic acid

The TFMSA=trifluoromethanesulfonic acid

The THF=oxolane.

Hereinafter for example understand synthetic method of the present invention.Except as otherwise noted, otherwise the implication of radicals R is given among formula I or the II as mentioned.

In one aspect of the invention, compound and about 3 hours of the reaction under heating of dicarboxylic acids, acetic anhydride and acetate mixture that the midbody compound of formula IIb can be by making formula IIa, cooling comes synthetic then:

R wherein ¹It is methyl.

Intermediate II c can be by the compound and for example chlorinated compound such as POCl that for example makes IIb ₃(having low amounts of water sometimes) react and heat about 4 hours, then the cooling prepare:

Intermediate II d can be by the compound and for example P in solvent such as DMF that makes IIc ¹-X and alkali such as K ₂CO ₃React and form in room temperature or under heating:

P wherein ¹Be blocking group [for example to methoxy-benzyl (PMB)]; X is leaving group such as halogen, methanesulfonic acid ester group (mesylate) or toluenesulfonic acid ester group (tosylate).

Intermediate II e can be by making IId compound and hydrazine or hydrazine hydrate in solvent such as methyl alcohol, react and reflux about 4 hours, cooling prepares then:

Intermediate compound IV a can be by compound and the POCl that for example makes IIe ₃React with DMF and to form:

R wherein ¹Such as among front formula I or the II definition, methyl for example.

Intermediate compound IV b can be by the compound and for example R in solvent such as DMF that makes IVa ₅-X and alkali such as K ₂CO ₃React and form in room temperature or under heating:

Intermediate compound IV c can be by removing blocking group P with suitable method ¹Compound by IVb is synthetic.For example, if P ¹Be the PMB group, then can be removed in room temperature with CAN or TFA/TFMSA:

Intermediate compound IV d can be prepared as follows: make the compound of IVc and for example chlorinated compound such as POCl ₃Reaction also refluxed about 2 days or uses microwave device in about 10 minutes of 150～200 ℃ of heating, cooling then in air-tight bottle:

Intermediate compound IV e can be by making IVd compound and amino alcohol under the alkali condition in solvent such as DMF reaction and heated overnight, cooling forms then:

Perhaps, intermediate compound IV e can be directly by the compound of IVc by in the presence of alkali such as DBU, reacting synthetic with amino alcohol and coupling reagent such as BOP:

Wherein all substituting groups such as front define.

Compound IV f can be by the compound and for example dehydrating agent/halogenating agent such as SOCl that makes IVe ₂At solvent such as CH ₂Cl ₂In in room temperature reaction spend the night or in 35 ℃ the heating a few hours, then the cooling form:

Compound IV g can be by making IVf compound and for example halogenating agent such as NCS and alkali such as LDA in solvent such as THF at low temperatures stoichiometric number hour form:

Perhaps, the compound that compound IV g can be by making IVf and for example halogenating agent such as carbon trichloride and alkali such as LiHMDS in solvent such as THF at low temperatures stoichiometric number hour form:

Compound I can be by compound and the R that makes IVg ₆-LH for example mercaptan reacts and forms under heating:

Perhaps, Compound I can be by compound and the mercaptan R that makes IVf ₆-LH or disulphide R ₆-L-L-R ₆In the presence of highly basic such as lithium reagent (for example LiHMDS), in solvent such as THF, react and form.

Corresponding sulfinyl or sulfonyl-derivatives can by make the 3-sulfur-based compound (for example wherein L be-S-) react in solvent such as acetonitrile in room temperature and form with oxidant such as peroxide (for example oxone or hydrogen peroxide).

Therefore, in another aspect of the present invention, the invention provides the method for preparation formula I or II compound, for example, it comprises makes Compound I-A and for example R in solvent such as DMF ₅-X and alkali such as K ₂CO ₃React in room temperature or under heating:

Wherein all substituting groups such as front define; X is leaving group such as halogen, methanesulfonic acid ester group or toluenesulfonic acid ester group.

Sulfur-based compound of the present invention, for example wherein L be the formula I of S or II compound or compound (I)-B can by make compound (IVf) for example with disulphide and two (TMS) lithium amides (lithium bis (trimethylsilyl) azanide, LiHMDS) reaction prepares:

Sulfinyl of the present invention or sulfonyl-derivatives, for example wherein L is SO or SO ₂Formula I or II can oxone oxidation (I)-B in solvent such as acetonitrile and methyl alcohol prepares by for example using.Use the method for compound of the present invention

Destruction or infringement that compound of the present invention can be used for treating with the approach of cAMP and cGMP mediation are the disease of feature, and the destruction of the approach of described cAMP and cGMP mediation or infringement for example are by synthetic inducer of cyclic nucleotide such as dopamine and nitrogen oxide (NO) suppresses or level reduces the PDE1 that causes and expresses increase or cAMP and cGMP and express the result who reduces.By preventing that PDE1B from causing cAMP and cGMP to degrade and also increasing level in the cell of cAMP and cGMP thus, compound of the present invention has strengthened the activity of the synthetic inducer of cyclic nucleotide.

The invention provides any one or multiple method in the following illness of treatment:

(i) neurodegenerative disease, comprise Parkinson's, how moving leg, tremble, movement disorder, Huntington, Alzheimer disease and drug-induced ataxia;

(ii) phrenoblabia comprises depression, attention deficit disorder, attention-deficit hyperactivity disease, bipolar disorder, anxiety, for example hypnolepsy of sleep-disorder, Cognitive function damage, dementia, tourette's syndrome, autism, fragile X syndrome, incitantia is given up and drug habit;

(iii) circulation and cardiovascular disorder comprise cranial vascular disease, apoplexy, CHD, hypertension, pulmonary hypertension and sex dysfunction;

(iv) respiratory system and inflammatory disorder comprise asthma, COPD and allergic rhinitis, and autoimmunity and inflammatory disease;

(v) low-level (the perhaps inhibition of cAMP and/or cGMP signal transduction path) with cAMP and/or cGMP in the cell of expressing PDE1 is any disease or the illness of feature; And/or

(be any disease or the illness of feature with the d1 dopamine receptor signaling activity that reduces vi), this method comprises to its human or animal patient of needs uses in the compound of the present invention, for example formula I of free form, pharmaceutically acceptable salt form or the prodrug forms of effective dose any one described compound among any one or the 11-1.76.In yet another aspect, the invention provides the method for treatment illness disclosed above, this method comprises the free form of administering therapeutic effective dose or the formula II compound of pharmaceutically acceptable salt form.

In an especially preferred embodiment, the invention provides treatment or prevent narcoleptic method.In this embodiment, the PDE1 inhibitor can be used as unique therapeutic agent, but also can use with other activating agent combination or use jointly.Therefore, the present invention also comprises the narcoleptic method of treatment, this method comprise to needs its human or animal patient simultaneously, in succession or the following substances of the free form of parallel administering therapeutic effective dose, pharmaceutically acceptable salt form or prodrug forms: (i) PDE1 inhibitor, for example among the formula I among any one or the 1.1-1.76 any one described compound and

(ii) promote the compound of awakening or regulation and control sleep, for example be selected from (a) central nervous system stimulus-amphetamine compound and amphetamine sample compound, for example methylphenidate, Dexamfetamine, crystal methamphetamine (methamphetamine) and pemoline; (b) modafinil, (c) antidepressants, for example tricyclics (comprising imipramine, desipramine, clomipramine and protriptyline) and selective serotonin reuptaking inhibitor (comprising Prozac and Sertraline); And/or (d) γ hydroxybutyric acid or γ hydroxybutyric acid salt (GHB).

In another embodiment, treatment mentioned above or prevent narcoleptic method to comprise the free form of administering therapeutic effective dose or the formula II compound mentioned above of pharmaceutically acceptable salt form, described compound share in using jointly as unique therapeutic agent or with other active groups.

In another embodiment, the present invention also provides the method for the illness that treatment or prevention can be alleviated by strengthening the conduction of progesterone signal, and this method comprises to its human or animal patient of needs uses in the compound of the present invention, for example formula I of free form, pharmaceutically acceptable salt form or the prodrug forms of effective dose any one described compound among any one or the 1.1-1.76.The present invention also provides methods of treatment disclosed herein, and this method comprises the free form of administering therapeutic effective dose or the formula II compound of pharmaceutically acceptable salt form.Can be by infertile, irregular menstrual cycle, AUB, osteoporosis, autoimmune disease, multiple sclerosis, prostate increase, prostate cancer and the hypothyroidism that strengthens that disease that the conduction of progesterone signal is enhanced or illness include but not limited to that female sex dysfunction, secondary amenorrhea (for example exercise related amenorrhea, no ovulation, menopause, menopausal symptom, hypothyroidism), premenstrual syndrome, premature labor, infertile for example recurrent abortion cause.For example, by strengthening the conduction of progesterone signal, the PDE1 inhibitor can be used to promote the implantation of ovum by the effect to the intrauterine layer, and can be used to help immune response or low progesterone function owing to gestation to have the women of miscarriage tendency to keep gestation.New PDE1 inhibitor, for example new PDE1 inhibitor as herein described also is used in the postmenopausal women validity that strengthens hormone replacement therapy, for example with oestrogenic hormone/estradiol/estriol and/or progesterone/progestogens combined administration, and the endometrial hyperplasia and the cancer that are used for oestrogenic hormone-induce.Method of the present invention also can be used for animal reproduction, for example to induce the property sensitivity and/or the estrus of inhuman female mammal to be bred.

In this embodiment, the PDE1 inhibitor can be used as unique therapeutic agent and is used for aforesaid treatment or prevention method, but also can use with other activating agent combination or use jointly, for example with the hormone replacement therapy coupling.Therefore, the present invention comprises that also treatment can be by strengthening the method for the obstacle that the conduction of progesterone signal is enhanced, this method comprise to needs its human or animal patient simultaneously, in succession or the following substances of the free form of parallel administering therapeutic effective dose, pharmaceutically acceptable salt form or prodrug forms:

(i) PDE1 inhibitor, for example among the formula I among any one or the 1.1-1.76 any one described compound and

(ii) hormone for example is selected from oestrogenic hormone and oestrogen-mimicking (for example estradiol, estriol, estradiol ester) and progesterone and progesterone analog (for example progestogens).

In another embodiment, the invention provides aforesaid method, wherein the PDE1 inhibitor is the formula II compound of free form or pharmaceutically acceptable salt form.

The present invention also provides and has strengthened or increased in the cell or tissue method of signaling activity in the dopamine D 1 cell, and this method comprises that the compound of any one contacts among compound of the present invention, for example formula I compound or the 1.1-1.76 that makes described cell or tissue and the amount that is enough to suppress the PDE1B activity.The present invention also provides and has strengthened or increased in the cell or tissue method of signaling activity in the dopamine D 1 cell, and this method comprises makes described cell or tissue contact with the free form of the amount that is enough to suppress PDE1 activity, for example PDE1A or PDE1B activity or the formula II compound of salt form.

The present invention also provides the method for the obstacle that the signal transduction path obstacle maybe can be alleviated by strengthening the progesterone signal transduction path in treatment PDE1-correlation obstacle, especially PDE1B-correlation obstacle, the d1 dopamine receptor cell in its patient of needs, this method comprises the compound of using among compound of the present invention, for example formula I compound or the 1.1-1.76 of the inhibition PDE1B of effective dose any one to the patient, the wherein active phosphorylation of regulating DARPP-32 and/or GluR1 ampa receptor of PDE1B.Similarly, the invention provides the method for the obstacle that the signal transduction path obstacle maybe can be alleviated by strengthening the progesterone signal transduction path in treatment PDE1-correlation obstacle, especially PDE1B-correlation obstacle, the d1 dopamine receptor cell in its patient of needs, this method comprises to the patient uses the free form of effective dose or the formula II compound mentioned above of pharmaceutically acceptable salt form.

In yet another aspect, the present invention also provides the method for the intraocular pressure of treatment glaucoma or rising, this method comprise to needs its patient's the free form of the treatment effective dose of eye local application in eye compatibility carrier or I type phosphodiesterase of the present invention (PDE1) inhibitor of pharmaceutically acceptable salt form.But treatment also can comprise constitutional treatment.Constitutional treatment comprises the treatment or the Orally administered method that for example can directly arrive blood flow.

The present invention also provides the pharmaceutical composition that topical ophthalmic is used that is used for that comprises the PDE1 inhibitor; For example ophthalmic solution, supensoid agent, cream or ointment, it comprises the ophthalmology acceptable diluent or the carrier of the PDE1 inhibitor of the present invention of free form or the acceptable salt form of ophthalmology and combination or associating with it.

Randomly, the PDE1 inhibitor can be used in succession or simultaneously with second kind of medicine that can be used for treating the intraocular pressure of glaucoma or rising.Under the situation of using two kinds of activating agents, the treatment effective dose of every kind of activating agent can be lower than the active required amount of generation in the monotherapy.Therefore, subthreshold value amount (that is, being lower than the amount that produces the required level of effect in the monotherapy) can be considered to treatment effectively, and also can be called as effective dose.In fact, the advantage of using the different activities agent with the different mechanisms of action and different side effect character can be to reduce dosage and the side effect and the enhancing of two kinds of medicines one or both of or increase their activity as monotherapy.

Therefore, the invention provides the method for the illness for the treatment of the intraocular pressure that is selected from glaucoma and rising, that this method comprises is parallel with the PDE1 inhibitor of the present invention of free form effective dose, for example subthreshold value amount or pharmaceutically acceptable salt form, needed its patient to use the activating agent of known reduction intraocular pressure effective dose, for example subthreshold value amount simultaneously or in succession, thereby makes that the amount of activating agent of known reduction intraocular pressure and the amount combination of PDE1 inhibitor are effective for this illness of treatment.

In one embodiment, two kinds of activating agents one or both of are locally applied to eye.Therefore, the invention provides the method for the side effect of the intraocular pressure treatment that reduces glaucoma or rising, this method be by parallel with the PDE1 inhibitor of effective dose, simultaneously or the sequential application activating agent that reduces the known reduction intraocular pressure of dosage carry out.But, also can adopt local application method such as whole body therapeutic in addition to use.

Optional one or more other activating agents that are used for being used in combination with the PDE1 inhibitor can for example be selected from existing medicine, typically comprise the carbonic anhydrase inhibitor such as the acetazolamide of prostaglandin, pilocarpinum, adrenergic instillation or local beta-blocker treatment (for example carrying out with timolol) and systemic administration.Also can adopt anticholinesterase such as eserine and echothiopate (echothiopate), they have the effect similar to pilocarpinum.Therefore, being used for the treatment of glaucomatous medicine at present for example comprises:

1. prostaglandin analogue such as Latanoprost (Xalatan), bimatoprost (Lumigan) and travoprost (Travatan), its uvea-sclera that increases aqueous humor flows out.Bimatoprost also increases girder and flows out.

2. local B-adrenergic receptor antagonist such as timolol, levobunolol (Betagan) and betaxolol, it reduces capsulociliary aqueous humor and produces.

3. α ₂-2-adrenergic agonist components such as Brimonidine (Alphagan), it works by double mechanism, promptly reduces the aqueous humor generation and increase uvea-sclera to flow out.

4. sympathetic transmitter releasers that selectivity is lower such as adrenaline and Dipivefrine (Propine) increase aqueous humor by trabecular network and the outflow that may flow out approach by the uvea sclera, and this may be to pass through β ₂The effect of-activator produces.

5. miotic (parasympathomimetics) works by the contraction of ciliary muscle as pilocarpinum, and making trabecular network become tight and aqueous humor is flowed out increases.

6. carbonic anhydrase inhibitor such as Dorzolamide (Trusopt), brinzolamide (Azopt), acetazolamide (Diamox) reduce the aqueous humor secretion by the carbonic anhydrase that suppresses in the ciliary body.

7. eserine also is used for the treatment of glaucoma and delayed gastric emptying.

For example, the invention provides the pharmaceutical composition that comprises PDE1 inhibitor of the present invention and be selected from following activating agent: (i) prostanoid, Unoprostone, Latanoprost, travoprost or bimatoprost; (ii) alpha-2-adrenergic agonist components such as Brimonidine, Apraclonldine or Dipivefrine and (iii) muscarinic agonist such as pilocarpinum.For example, the invention provides eye-drops preparations, it comprises PDE-1 inhibitor of the present invention and bimatoprost, abrimonidine, Brimonidine, timolol or its combination of free form or the acceptable salt form of ophthalmology, and the ophthalmology acceptable diluent or the carrier that make up or unite with it.But except selecting combination, those of ordinary skills can select the selective receptor subtype agonist or the antagonist that suit.For example, for alpha-2-adrenergic agonist components, those of ordinary skills for example can select α 1 adrenergic receptor activator or to alpha 2-adrenoceptor selectively activator such as Brimonidine selectively.For the B-adrenergic receptor antagonist, those of ordinary skills can be according to suitable treatment application choice to β ₁Or β ₂Or β ₃Antagonist selectively.Those of ordinary skills also can select special receptor hypotype such as M ₁-M ₅Muscarinic agonist selectively.

The PDE1 inhibitor can be used with the form of ophthalmic composition, and described ophthalmic composition comprises ophthalmic solution, cream or ointment.Ophthalmic composition can comprise the activating agent that reduces intraocular pressure in addition.

In another embodiment, disclosed PDE-1 inhibitor can with the activating agent combination of the reduction intraocular pressure of subthreshold value amount, described activating agent can be bimatoprost ophthalmic solution, brimonidine tartrate ophthalmic solution or brimonidine tartrate/timolol maleate ophthalmic solution.

Except said method, also it has surprisingly been found that, the PDE1 inhibitor can be used for treating mental disease, be any illness for example schizophrenia, schizoaffective disorder, schizophreniform disorder, psychotic disease phrenoblabia, the delusional disorder and manic of feature for example, for example in treatment of acute manic episode and bipolar disorder with psychotic symptoms such as illusion, paranoid or strange vain hope or speech and disturbance in thinking.Be not intended to be bound by any theory, it is believed that typical case and atypical antipsychotic agents such as Clozapine mainly have their antagonistic activity on d2 dopamine receptor.But the PDE1 inhibitor mainly works on d1 dopamine receptor to strengthen the signal conduction.By strengthening the conduction of D1 receptor signal, the PDE1 inhibitor can strengthen each brain zone and for example lie prostrate nmda receptor function in nucleus neuron and the prefrontal cortex.This increased functionality can for example see in the nmda receptor that contains the NR2B subunit, and can be for example takes place via the kinase whose activation of Src and protein kinase A family.

Therefore, the invention provides the new method of treatment mental case such as schizophrenia, schizoaffective disorder, schizophreniform disorder, psychotic disease phrenoblabia, delusional disorder and manic (for example in maniac access and bipolar disorder), this method comprise to needs its free form of patient's administering therapeutic effective dose or phosphodiesterase of the present invention-1 (PDE1) inhibitor of pharmaceutically acceptable salt form.

The PDE1 inhibitor can be used as unique therapeutic agent and is used for aforementioned therapies or prevention method, but also can use with other activating agent combination or use jointly.Therefore, the present invention also comprises treatment mental case such as schizophrenia, schizoaffective disorder, schizophreniform disorder, psychotic disease phrenoblabia, delusional disorder or manic method, this method comprise to needs its patient simultaneously, in succession or parallel administering therapeutic effective dose:

(i) the PDE1 inhibitor of the present invention of free form or pharmaceutically acceptable salt form; With

The (ii) antipsychotic drug of free form or pharmaceutically acceptable salt form, for example

Typical case's antipsychotic drug, for example

Butyrophenones, for example haloperole (Haldol, Serenace), droperidol (Droleptan);

Phenothiazines, chlorpromazine (Thorazine for example, Largactil), fluphenazinum (Prolixin), perphenazine (Trilafon), prochlorperazine (Compazine), thioridazine (Mellaril, Melleril), triperazine (Stelazine), mesoridazine, pericyazine, promazine, padil (Vesprin), levomepromazine (Nozinan), fenazil (Phenergan), Pimozide (Orap);

The thioxanthene class, for example Chlorprothixene, depixol (Depixol, Fluanxol), thiothixene (Navane), Zuclopenthixol (Clopixol, Acuphase);

Atypical antipsychotic agents, for example

Clozapine (Clozaril), Olanzapine (Zyprexa), Risperidone (Risperdal), Quetiapine (Seroquel), Ziprasidone (Geodon), Amisulpride (Solian), Paliperidone (Invega), Aripiprazole (Abilify), Bifeprunox; Norclozapine.

In a specific embodiment, compound of the present invention is particularly useful for treatment or prevention schizophrenia.

The compound of the present invention of free form or pharmaceutically acceptable salt form is particularly useful for treating Parkinson's, schizophrenia, hypnolepsy, glaucoma and female sex dysfunction.

In yet another aspect, the invention provides the method that prolongs or strengthen the eyelashes growth, this method be by parallel with the PDE1 inhibitor of the present invention of the free form of effective dose or pharmaceutically acceptable salt form, simultaneously or in succession give prostaglandin analogue that the patient's who needs it eye uses effective dose for example bimatoprost carry out.

In yet another aspect, the invention provides the method for treatment or prevention traumatic brain injury, this method comprise to needs its free form of patient's administering therapeutic effective dose or the PDE1 inhibitor of the present invention of pharmaceutically acceptable salt form.Traumatic brain injury (TBI) is contained primary injury and secondary lesion, has both comprised focal brain damage, comprises the dispersivity brain damage again.Secondary lesion is multiple, parallel, the interactional and complementary cascade that produces from the biological respinse of discrete subcellular fraction process (for example excessive inflow of the stimulation oversaturation of the toxicity that is caused by active oxygen, glutamate receptor, calcium and inflammatory incremental adjustments), described subcellular fraction process after by initial (primary) damage inflammatory response and process causes or by its aggravation.Unusual calcium homeostasis it is believed that it is the key factor of grey matter and white matter secondary lesion progress in the two.About the summary of TBI, referring to people such as Park, CMAJ (2008) 178 (9): 1163-1170 is incorporated herein by reference its content whole.Study verifiedly, the cAMP-PKA signal transduction cascade is reduced behind TBI, and treating with PDE IV inhibitor such as rolipram behind TBI increases or recover the cAMP level and improve the histopathology result and reduce inflammation.Because compound of the present invention is the PDE1 inhibitor, thinks that these compounds also can be used for treating TBI, for example behind traumatic brain injury, treat TBI by recovering cAMP level and/or calcium homeostasis.

The present invention also provides:

(i) compound of any one or formula II among compound of the present invention mentioned above, for example formula I or the 1.1-1.76 of free form, pharmaceutically acceptable salt form or prodrug forms, any means that it is used for above providing or any disease or the treatment of conditions that above provide;

(ii) the compound of any one or formula II is used for the treatment of purposes in the medicament of any disease that above provides or illness in preparation among compound of the present invention mentioned above, for example formula I or the 1.1-1.76 of free form, pharmaceutically acceptable salt form or prodrug forms;

(iii) pharmaceutical composition, it comprises among compound of the present invention mentioned above, for example formula I or the 1.1-1.76 of free form, pharmaceutically acceptable salt form or prodrug forms the compound of any one or formula II and the pharmaceutically acceptable diluent or carrier of combination or associating with it; With

(iv) be used for the treatment of any disease that above provides or the pharmaceutical composition of illness, it comprises among compound of the present invention mentioned above, for example formula I or the 1.1-1.76 of free form, pharmaceutically acceptable salt form or prodrug forms the compound of any one or formula II and the pharmaceutically acceptable diluent or carrier of combination or associating with it.

Therefore, the compound of the present invention that the invention provides among compound of the present invention mentioned above, for example formula I or the 1.1-1.76 of free form, pharmaceutically acceptable salt form or prodrug forms the compound of any one or formula II or pharmaceutical compositions is used for the treatment of or prevents purposes in the medicament of following disease in preparation: Parkinson's, how moving leg, tremble, movement disorder, Huntington, Alzheimer disease and drug-induced ataxia; Depression, attention deficit disorder, attention-deficit hyperactivity disease, bipolar disorder, anxiety, sleep-disorder, hypnolepsy, Cognitive function damage, dementia, tourette's syndrome, autism, fragile X syndrome, incitantia is given up and/or drug habit; Cranial vascular disease, apoplexy, CHD, hypertension, pulmonary hypertension and/or sex dysfunction; Asthma, COPD and/or allergic rhinitis and autoimmunity and inflammatory disease; And/or the endometrial hyperplasia or the cancer of female sex dysfunction, exercise related amenorrhea, no ovulation, menopause, menopausal symptom, hypothyroidism, premenstrual syndrome, premature labor, infertile, irregular menstrual cycle, AUB, osteoporosis, multiple sclerosis, prostate increase, prostate cancer, hypothyroidism, oestrogenic hormone-induce; And/or be feature and/or be any disease or the illness of feature with the d1 dopamine receptor signaling activity of reduction with low-level (the perhaps inhibition of cAMP and/or cGMP signal transduction path) of cAMP and/or cGMP in expressing the cell of PDE1; And/or can be by strengthening any disease or the illness that the conduction of progesterone signal is enhanced.

The present invention also provides the purposes of compound of the present invention in the preparation medicament of free form or pharmaceutically acceptable salt form, and described medicament is used for the treatment of or prevents:

A) intraocular pressure of glaucoma or rising,

B) mental disease, be any illness of feature for example with psychotic symptoms such as illusion, paranoid or strange vain hope or speech and disturbance in thinking, for example schizophrenia, schizoaffective disorder, schizophreniform disorder, psychotic disease phrenoblabia, delusional disorder and manic, for example in treatment of acute manic episode and bipolar disorder

C) traumatic brain injury.

Phrase " compound of the present invention " or " PDE1 inhibitor of the present invention " contain disclosed herein arbitrarily and all compounds, the compound of any one or formula II among formula I mentioned above or the 1.1-1.76 for example, described compound is free form or salt form.

Therefore, wording " treatment " is understood to include the prevention of disease symptoms and the treatment of treatment or the improvement and the disease cause of disease.

For methods of treatment, wording " effective dose " is intended to contain the treatment effective dose of treatment specified disease or obstacle.

It is too high that term " pulmonary hypertension " is intended to contain the pulmonary artery blood pressure.

Term " patient " comprises people or inhuman (being animal) patient.In specific embodiment, people and inhuman is contained in the present invention.In another embodiment, the present invention is contained inhuman.In other embodiments, the people contained in this term.

Used term " comprises " that to be intended to be open in the disclosure thing, does not get rid of other key element of not addressing or method step.

Compound of the present invention is particularly useful for treating Parkinson's, hypnolepsy and female sex dysfunction.

The compound of any one or formula II can be used as unique therapeutic agent among the compound of the present invention of free form or pharmaceutically acceptable salt form, for example formula I or the 1.1-1.76, but also can use with other activating agent combination or use jointly.For example, because compound of the present invention strengthens the activity of D1 activator such as dopamine, they can with the dopaminergic medication of routine such as levodopa and levodopa adminicle (adjunct) (carbidopa, COMT inhibitor, MAO-B inhibitor), dopamine agonist and anticholinergic agent simultaneously, in succession or parallel using, for example in the treatment of suffering from Parkinsonian patient.In addition, new PDE1 inhibitor, for example new PDE1 inhibitor as herein described also can with oestrogenic hormone/estradiol/estriol and/or progesterone/progestogens combined administration to strengthen hormone replacement therapy or the oestrogenic hormone-endometrial hyperplasia of inducing or the validity of cancer treatment.

Implementing the used dosage of the present invention will change according to disease specific for example to be treated or illness, used concrete compound of the present invention, mode of administration and required therapy certainly.Compound of the present invention can be used by any suitable way, comprises that oral, stomach and intestine are outer, transdermal or use by suction, but preferred oral is used.Generally speaking, use demonstration with about 0.01 to 2.0mg/kg other oral dose of level and can obtain gratifying result, for example for treating above given disease.Therefore, for example among the people, being used for the Orally administered daily dose that is suitable for will be in about 0.75 to 150mg scope bigger mammal, and it can be used once a day easily or use 2 to 4 times or use with the slowly-releasing form every day with divided dose.Therefore, be used for Orally administered unit dosage forms and for example can comprise about 0.2 to 75 or 150mg, for example about 0.2 or 2.0 to 50,75 or 100mg compound of the present invention and pharmaceutically acceptable diluent or carrier.

The pharmaceutical composition that comprises compound of the present invention can adopt conventional thinner known in the galenica field or excipient and technology to prepare.Therefore, peroral dosage form can comprise tablet, capsule, solution and supensoid agent etc.

Embodiment

Hereinafter for example understand the synthetic method of various compounds of the present invention.The salt of other compound of the present invention and they can adopt with hereinafter described similarly method and/or by with those similar methods of being summarized in the part are described in detail in detail and make by the known method of chemical field.

Embodiment 1:

(6aR, 9aS)-5,6a, 7,8,9,9a-six hydrogen-5-methyl-3-(phenyl sulfenyl)-2-(4-(6-fluorine pyridine-2-yl) benzyl)-cyclopenta [4,5] imidazo [1,2-a] pyrazolo [4,3-e] pyrimidines-4 (2H)-ketone

Will (6aR, 9aS)-5,6a, 7,8,9,9a-six hydrogen-5-methyl-2-(4-(6-fluorine pyridine-2-yl) benzyl)-cyclopenta [4,5] imidazo [1,2-a] and pyrazolo [4,3-e] pyrimidines-4 (2H)-ketone (56.8mg, 0.136mmol) and phenyl disulfide (59.6mg, 0.273mmol) be dissolved among the anhydrous THF of 1mL, drip the solution of 273uL1.0M LiHMDS in THF then.Reactant mixture in stirring at room 1 hour, is used the salt solution cancellation then.Mixture is separated with half preparation HPLC, obtain the 27mg pure products, be yellow solid.MS(ESI)m/z?525.2[M+H] ⁺。

Embodiment 2:

(6aR, 9aS)-5,6a, 7,8,9,9a-six hydrogen-5-methyl-3-(phenyl sulfinyl)-2-(4-(6-fluorine pyridine-2-yl) benzyl)-cyclopenta [4,5] imidazo [1,2-a] pyrazolo [4,3-e] pyrimidines-4 (2H)-ketone

Will (6aR, 9aS)-5,6a, 7,8,9, (12mg 0.023mmol) is dissolved in CH to 9a-six hydrogen-5-methyl-3-(phenyl sulfenyl)-2-(4-(6-fluorine pyridine-2-yl) benzyl)-cyclopenta [4,5] imidazo [1,2-a] pyrazolo [4,3-e] pyrimidines-4 (2H)-ketone ₃CN (2mL) and CH ₃Among the OH (2mL), add the aqueous solution of oxone then.Reactant mixture in 1 week of stirring at room, by half preparation HPLC purifying, is obtained pure products then, be white solid.MS(ESI)m/z?541.2[M+H] ⁺。

Embodiment 3:

(6aR, 9aS)-5,6a, 7,8,9,9a-six hydrogen-5-methyl-3-(methyl sulfenyl)-2-(4-(6-fluorine pyridine-2-yl) benzyl)-cyclopenta [4,5] imidazo [1,2-a] pyrazolo [4,3-e] pyrimidines-4 (2H)-ketone

Will (6aR, 9aS)-5,6a, 7,8,9,9a-six hydrogen-5-methyl-2-(4-(6-fluorine pyridine-2-yl) benzyl)-cyclopenta [4,5] imidazo [1,2-a] and pyrazolo [4,3-e] pyrimidines-4 (2H)-ketone (50mg, 0.12mmol) and methyl disulfide (21.3 μ L, 0.24mmol) be dissolved among the anhydrous THF of 1mL, drip the solution of 360uL 1.0MLDA in THF then.Reactant mixture in stirring at room 1 hour, is used the salt solution cancellation then.Mixture is separated with half preparation HPLC, obtain the 6.8mg pure products, be light yellow solid.MS(ESI)m/z?463.2[M+H] ⁺。

Embodiment 4:

(6aR, 9aS)-5,6a, 7,8,9,9a-six hydrogen-3-(methyl sulfenyl)-2-(4-(6-fluorine pyridine-2-yl) benzyl)-cyclopenta [4,5] imidazo [1,2-a] pyrazolo [4,3-e] pyrimidines-4 (2H)-ketone

Will (6aR, 9aS)-5,6a, 7,8,9,9a-six hydrogen-5-methyl-3-(methyl sulfenyl)-2-(4-(6-fluorine pyridine-2-yl) benzyl)-cyclopenta [4,5] imidazo [1,2-a] pyrazolo [4,3-e] pyrimidines-4 (2H)-ketone (25mg, 0.054mmol) and P ₄S ₁₀(48.1mg 0.108mmol) places Biotage microwave bottle, adds the solution of 1.0mL7N ammonia in MeOH then.Sealed vial was heated 6 hours in 150 ℃ in the Biotage micro-wave oven.Except that after desolvating, residue is suspended among the DMF, filter then.Gained filtrate by half preparation HPLC purifying, is obtained the 10.6mg pure products, be light yellow solid (productive rate: 44%).MS(ESI)m/z?449.2[M+H] ⁺。

Embodiment 5:

(6aR, 9aS)-5,6a, 7,8,9,9a-six hydrogen-3-(pyridine-2-base sulfenyl)-2-(4-(6-fluorine pyridine-2-yl) benzyl)-cyclopenta [4,5] imidazo [1,2-a] pyrazolo [4,3-e] pyrimidines-4 (2H)-ketone

The synthetic operation of this compound is similar to Example 1, wherein uses two sulphur two (2-pyridine radicals) (2-pyridyl disulfide) to replace phenyl disulfide.MS(ESI)m/z?526.2[M+H] ⁺。

Embodiment 6:

(6aR, 9aS)-5,6a, 7,8,9,9a-six hydrogen-5-methyl-3-((R)-methylsulfinyl)-2-(4-(6-fluorine pyridine-2-yl) benzyl)-cyclopenta [4,5] imidazo [1,2-a] pyrazolo [4,3-e] pyrimidines-4 (2H)-ketone

Will (6aR, 9aS)-5,6a, 7,8,9,9a-six hydrogen-5-methyl-3-(methyl sulfenyl)-2-(4-(6-fluorine pyridine-2-yl) benzyl)-cyclopenta [4,5] imidazo [1,2-a] (35.2mg 0.076mmol) is dissolved in CH to pyrazolo [4,3-e] pyrimidines-4 (2H)-ketone ₃CN (0.5mL) and CH ₃Among the OH (2mL), add oxone (93.7mg, aqueous solution 0.152mmol) then.Reactant mixture in stirring at room 20 hours, by half preparation HPLC purifying, is obtained pure products then, be white solid.MS(ESI)m/z?479.2[M+H] ⁺。

Embodiment 7:

(6aR, 9aS)-5,6a, 7,8,9,9a-six hydrogen-5-methyl-3-((S)-methylsulfinyl)-2-(4-(6-fluorine pyridine-2-yl) benzyl)-cyclopenta [4,5] imidazo [1,2-a] pyrazolo [4,3-e] pyrimidines-4 (2H)-ketone

The synthetic operation of this compound is identical with embodiment 6.Between synthesis phase, obtained a pair of diastereoisomer.Two kinds of diastereo-isomerism physical efficiencys are separated with achiral reversed-phase HPLC post.Obtain product, be white solid.MS(ESI)m/z?479.2[M+H] ⁺。

Embodiment 8:

(6aR, 9aS)-5,6a, 7,8,9,9a-six hydrogen-5-methyl-3-(methyl sulphonyl)-2-(4-(6-fluorine pyridine-2-yl) benzyl)-cyclopenta [4,5] imidazo [1,2-a] pyrazolo [4,3-e] pyrimidines-4 (2H)-ketone

(6aR, 9aS)-5,6a, 7,8,9, (4-(6-fluorine pyridine-2-yl) benzyl)-(35.2mg 0.076mmol) is dissolved in CH to cyclopenta [4,5] imidazo [1,2-a] pyrazolo [4,3-e] pyrimidines-4 (2H)-ketone to 9a-six hydrogen-5-methyl-3-(methyl sulfenyl)-2- ₃CN (0.5mL) and CH ₃Among the OH (2mL), add oxone (139mg, aqueous solution 0.226mmol) then.Reactant mixture in stirring at room 2 days, by half preparation HPLC purifying, is obtained pure products then, be white solid.MS(ESI)m/z?495.2[M+H] ⁺。

Embodiment 9

Use IMAP di-phosphate ester enzymatic determination kit in-vitro measurements PDE1B to suppress

Phosphodiesterase 1B (PDE1B) be cyclic guanosine list phosphoric acid (cGMP) is converted into 5 '-guanosine monophosphate (5 '-GMP) calcium/calmodulin-dependent phosphodiesterase.PDE1B can also be converted into corresponding GMP-fluorescein with cGMP substrate, for example fluorescence molecule cGMP-fluorescein of modifying.Generating the GMP-fluorescein by the cGMP-fluorescein for example can adopt IMAP (CA) the affine particulate reagent of fixing metal carries out quantitatively for Molecular Devices, Sunnyvale.

In brief, free 5 '-phosphoric acid of not finding in the cGMP-fluorescein with finding in the GMP-fluorescein with high-affinity of IMAP reagent combines.GMP-fluorescein-IMAP the compound of gained is with respect to the cGMP-fluorescein and Yan Shida.The little fluorogen of combination can distinguish with unconjugated fluorogen in compound big, slowly reversing, because the photon that they are launched when fluorescing has kept the photon identical polarity used with fluorescence excitation.

In the di-phosphate ester enzyme assay, can not combine with IMAP and thereby the cGMP-fluorescein that keeps fluorescence polarization hardly be converted into the GMP-fluorescein, the GMP-fluorescein makes fluorescence polarization (Δ mp) produce big increase when combining with IMAP.Therefore, with the inhibition that reduces to detect phosphodiesterase of Δ mp.

Enzyme assay

Material: remove outside the IMAP reagent (reaction buffer, binding buffer liquid, FL-GMP and IMAP globule), all chemical substances all derive from Sigma-Aldrich (St.Louis, MO), IMAP reagent derive from molecule Molecular Devices (Sunnyvale, CA).

Determination method: with 3 ', 5 '-cyclic nucleotide specificity ox brain phosphodiesterase (Sigma, St.Louis, MO) with 50% glycerine reconstruct to 2.5U/ml.In 30 ℃, pH 7.5 times, the enzyme per minute of 1 unit is hydrolyzed to 5 '-AMP with 1.0 μ mol, 3 ', 5 '-cAMP.A enzyme is added 1999 parts of reaction buffer (30 μ M CaCl ₂, 10U/ml calmodulin (Sigma P2277), 10mM Tris-HCl pH 7.2,10mM MgCl ₂, 0.1%BSA, 0.05%NaN ₃) in, obtain the final concentration of 1.25mU/ml.The enzyme solutions of 99 μ l dilution is added in each hole of flat 96 hole polyethylene boards, be dissolved in the test compound of 100%DMSO to wherein adding 1 μ l.Compound and enzyme mixed be incorporated in the room temperature preincubate 10 minutes.

In 384 hole microtiter plates, cause the FL-GMP conversion reaction by merging 4 parts of enzymes and inhibitor mixed thing and 1 part of substrate solution (0.225 μ M).Reactant was in the dark hatched 15 minutes in room temperature.In each hole of 384 orifice plates, add 60 μ l binding reagents (the IMAP globule is being supplemented with 1: 400 dilution in the binding buffer liquid of 1: 1800 defoamer dilution) and stop reaction.With plate in incubated at room 1 hour so that IMAP is incorporated into to be walked to fully, place then Envision multi-mode micro plate reader (PerkinElmer, Shelton, CT) in to measure fluorescence polarization (Δ mp).

The inhibition of PDE activity is represented in the reduction of the GMP concentration that records with Δ mp reduction form.By at 0.0037nM to 80, the compound of 8 to 16 concentration in the 000nM scope exists to be measured enzymic activity down, maps with drug concentration-Δ mP and measure IC then ₅₀Value, it makes can use nonlinear regression software (XLFit; IDBS, Cambridge MA) estimates IC ₅₀Value.

Can select and suppress active at PDE1 as herein described or that be similar in the determination method as herein described test compound of the present invention.The common IC of the compound of embodiments of the invention ₅₀Value is less than 1 μ M, and for example, some are less than 250nM, and some are less than 10nM, and some are less than 5nM, and for example, embodiment 1,2 and 3 compound have the IC less than 250nM usually ₅₀Value.

Embodiment 10

The PDE1 inhibitor is to the influence of female rats reaction

Can be as people such as Mani, measure of the influence of PDE1 inhibitor described in Science (2000) 287:1053 to the reaction of female rats lordosis.Give 2 μ g oestrogenic hormone in advance with the wild type rat of oophorectomize and cannulate, 24 hours hindbrain indoor (icv) injections progesterone (2 μ g), PDE1 inhibitor of the present invention (0.1mg, 1.0mg or 2.5mg) or sesame oil solvents (contrast).Test the lordosis reaction of these rats in the presence of male rat.With lordosis merchant (LQ=lordosis number of times/10 times ride * 100) to lordosis reaction carry out quantitatively.

Claims

1. the optional substituted 3-of free form or salt form (sulfenyl, sulfinyl or sulfonyl)-7; 8-dihydro-(1H or 2H)-imidazo [1; 2-a] pyrazolo [4; 3-e] pyrimidine-4 (5H)-ketone or substituted 3-(sulfenyl, sulfinyl or sulfonyl)-7; 8; 9-three hydrogen-(1H or 2H)-pyrimido [1,2-a] pyrazolo [4,3-e] pyrimidines-4 (5H)-ketone.

2. compound according to claim 1, wherein said compound are the compounds of formula II:

Formula II

Wherein

(i) L is S, SO or SO ₂

(ii) R ₁Be H or C _1-4Alkyl (for example methyl or ethyl);

Perhaps

R ₂Be H and R ₃And R ₄Form two together-, three-or four-methylene bridge,

(iv)R ₅

A) be-D-E-F, wherein:

F is

H，

Aryl (for example phenyl),

Halogen (for example F, Br, Cl),

Halo C _1-4Alkyl (for example trifluoromethyl),

-C(O)-R ₁₅，

-N(R ₁₆)(R ₁₇)，

-S (O) ₂R ₂₁, or

Halogen (for example F, Cl or Br),

C _1-4Alkyl (for example methyl),

Halo C _1-4Alkyl (for example trifluoromethyl),

B) be substituted heteroaryl alkyl, for example replaced by haloalkyl;

Formula A

Halogen,

C _1-4Alkyl,

C _3-7Cycloalkyl,

Assorted C _3-7Cycloalkyl (for example pyrrolidinyl or piperidyl),

C _1-4Haloalkyl (for example trifluoromethyl),

Aryl (for example phenyl),

Aryl carbonyl (for example benzoyl),

Alkyl sulphonyl (for example methyl sulphonyl),

The heteroaryl carbonyl, or

Alkoxy carbonyl,

(v) R ₆Be

H，

C _1-4Alkyl (for example methyl),

C _3-7Cycloalkyl (for example cyclopenta),

Aryl (for example phenyl),

Heteroaryl (for example pyridine radicals, as pyridin-4-yl),

Aryl C _1-4Alkyl (for example benzyl),

Arylamino (for example phenyl amino),

Heteroaryl amino,

N, N-two C _1-4Alkyl amino,

N, the N-ammonia diaryl base,

-N(R ₁₈)(R ₁₉)；

(vi) n=0 or 1;

(ix) R ₁₆And R ₁₇Be H or C independently _1-4Alkyl;

(xi) R ₂₀Be H, C _1-4Alkyl (for example methyl) or C _3-7Cycloalkyl,

(xii) R ₂₁Be C _1-6Alkyl;

Described compound is free form, salt form or prodrug forms.

3. compound according to claim 1, wherein said compound are the compounds of formula I:

Formula I

Wherein

(i) L is singly-bound, S, SO or SO ₂

(ii) R ₁Be H or C _1-4Alkyl (for example methyl or ethyl);

Perhaps

(iv)R ₅

A) be-D-E-F, wherein:

F is H, aryl (for example phenyl), heteroaryl (for example pyridine radicals, di azoly, triazolyl, as pyridine-2-base, imidazoles-1-base, 1,2,4-triazol-1-yl), halogen (for example F, Br, Cl), halo C _1-4Alkyl (for example trifluoromethyl) ,-C (O)-R ₁₅,-N (R ₁₆) (R ₁₇) ,-S (O) ₂R ₂₁Or optional contain the C that at least one is selected from the atom of N or O _3-7Cycloalkyl (for example cyclopenta, cyclohexyl, pyrrolidinyl (for example pyrrolidines-3-yl), tetrahydrochysene-2H-pyrans-4-base or morpholinyl);

Wherein D, E and F are independently with randomly by one or more halogens (for example F, Cl or Br), C _1-4Alkyl (for example methyl), halo C _1-4Alkyl (for example trifluoromethyl) replaces, for example, F is a heteroaryl, pyridine radicals for example, it is replaced by one or more following groups: halogen (for example 6-fluorine pyridine-2-base, 5-fluorine pyridine-2-base, 6-fluorine pyridine-2-base, 3-fluorine pyridine-2-base, 4-fluorine pyridine-2-base, 4,6-dichloropyridine-2-yl), halo C _1-4Alkyl (for example 5-5-flumethiazine-2-yl) or C _1-4Alkyl (for example 5-picoline-2-yl), perhaps F is an aryl, phenyl for example, it is replaced (for example 4-fluorophenyl) by one or more halogens, and perhaps F is C _3-7Heterocyclylalkyl (for example pyrrolidinyl), it is optional by C _1-6Alkyl replaces (for example 1-methylpyrrolidin-3-yl); Perhaps

B) be substituted heteroaryl alkyl, for example replaced by haloalkyl;

Formula A

(v) R ₆Be

H，

C _1-4Alkyl,

C _3-7Cycloalkyl (for example cyclopenta),

Aryl (for example phenyl),

Heteroaryl (for example pyridine radicals, as pyridin-4-yl),

Aryl C _1-4Alkyl (for example benzyl),

Arylamino (for example phenyl amino),

Heteroaryl amino,

N, N-two C _1-4Alkyl amino,

N, the N-ammonia diaryl base,

-N(R ₁₈)(R ₁₉)；

(vi) n=0 or 1;

(ix) R ₁₆And R ₁₇Be H or C independently _1-4Alkyl;

(x) R ₁₈And R ₁₉Be H, C independently _1-4Alkyl or aryl (for example phenyl), wherein said aryl is optional by one or more following groups replacements: halogen (for example fluorophenyl, as the 4-fluorophenyl) or hydroxyl (for example hydroxy phenyl, as 4-hydroxy phenyl or 2-hydroxy phenyl);

(xi) R ₂₀Be H, C _1-4Alkyl (for example methyl) or C _3-7Cycloalkyl,

(xii) R ₂₁Be C _1-6Alkyl.

4. according to claim 1,2 or 3 described compounds, it is selected from following any compound:

Described compound is free form or salt form.

5. according to claim 1,2 or 3 described compounds, it is selected from following any compound:

Described compound is free form or salt form.

6. pharmaceutical composition, the pharmaceutically acceptable diluent or carrier that it comprises any described compound among the claim 1-5 and mixes with it.

7. treat in the following illness any one method: Parkinson's, how moving leg, tremble, movement disorder, Huntington, Alzheimer disease and drug-induced ataxia; Depression, attention deficit disorder, attention-deficit hyperactivity disease, bipolar disorder, anxiety, sleep-disorder, hypnolepsy, Cognitive function damage, dementia, tourette's syndrome, autism, fragile X syndrome, incitantia is given up and/or drug habit; Cranial vascular disease, apoplexy, CHD, hypertension, pulmonary hypertension and/or sex dysfunction; Asthma, COPD and/or allergic rhinitis, and autoimmunity and inflammatory disease; And/or the endometrial hyperplasia or the cancer of female sex dysfunction, exercise related amenorrhea, no ovulation, menopause, menopausal symptom, hypothyroidism, premenstrual syndrome, premature labor, infertile, irregular menstrual cycle, AUB, osteoporosis, multiple sclerosis, prostate increase, prostate cancer, hypothyroidism, oestrogenic hormone-induce; And/or be feature and/or be any disease or the illness of feature with the d1 dopamine receptor signaling activity of reduction with low-level (the perhaps inhibition of cAMP and/or cGMP signal transduction path) of cAMP and/or cGMP in expressing the cell of PDE1; And/or can be by strengthening any disease or the illness that the conduction of progesterone signal is enhanced; This method comprises that the patient to this treatment of needs uses any described compound or the described pharmaceutical composition of claim 6 among the claim 1-5 of effective dose.

8. the method for claim 7, wherein said illness is Parkinson's.

9. the method for claim 7, wherein said illness is a Cognitive function damage.

10. the method for claim 7, wherein said illness is hypnolepsy.

11. the method for claim 10, it also comprises to its patient of needs uses one or more compounds that are selected from central nervous system stimulus, modafinil, antidepressants and γ hydroxybutyric acid or γ hydroxybutyric acid salt.

12. the method for claim 7, wherein said illness are female sex dysfunctions.

13. the method for claim 12, it also comprises to its patient of needs uses one or more compounds that are selected from estradiol, estriol, estradiol ester, progesterone and progestogens.

14. the method for the intraocular pressure of treatment glaucoma or rising, this method comprise to needs its patient's the free form of the treatment effective dose of eye local application in eye compatibility carrier or the claim 1-5 of pharmaceutically acceptable salt form in any described compound.

15. treatment mental disease, schizophrenia, schizoaffective disorder, schizophreniform disorder, psychotic disease phrenoblabia, delusional disorder and manic, the method in treatment of acute manic episode and bipolar disorder for example, this method comprise to needs its free form of patient's administering therapeutic effective dose or the claim 1-5 of pharmaceutically acceptable salt form in any described compound.

16. comprising to its patient of needs, the method for treatment traumatic brain injury, this method use any described compound among the claim 1-5 of free form or pharmaceutically acceptable salt form.

17. prolong or strengthen the method for eyelashes growth, this method by with the claim 1-5 of the free form of effective dose or salt form in any described compound parallel, simultaneously or the prostaglandin analogue of sequential application effective dose for example bimatoprost carry out.

18. any described compound or the described pharmaceutical composition of claim 6 are used for the treatment of or prevent purposes in the medicament of following disease in preparation among the claim 1-5 of free form or pharmaceutically acceptable salt form: Parkinson's, how moving leg, tremble, movement disorder, Huntington, Alzheimer disease and drug-induced ataxia; Depression, attention deficit disorder, attention-deficit hyperactivity disease, bipolar disorder, anxiety, sleep-disorder, hypnolepsy, Cognitive function damage, dementia, tourette's syndrome, autism, fragile X syndrome, incitantia is given up and/or drug habit; Cranial vascular disease, apoplexy, CHD, hypertension, pulmonary hypertension and/or sex dysfunction; Asthma, COPD and/or allergic rhinitis, and autoimmunity and inflammatory disease; And/or the endometrial hyperplasia or the cancer of female sex dysfunction, exercise related amenorrhea, no ovulation, menopause, menopausal symptom, hypothyroidism, premenstrual syndrome, premature labor, infertile, irregular menstrual cycle, AUB, osteoporosis, multiple sclerosis, prostate increase, prostate cancer, hypothyroidism, oestrogenic hormone-induce; And/or be feature and/or be any disease or the illness of feature with the d1 dopamine receptor signaling activity of reduction with low-level (the perhaps inhibition of cAMP and/or cGMP signal transduction path) of cAMP and/or cGMP in expressing the cell of PDE1; And/or can be by strengthening any disease or the illness that the conduction of progesterone signal is enhanced.

19. any described compound or the described pharmaceutical composition of claim 6 are used for the treatment of or prevent to be selected from purposes in the medicament of following disease or illness in preparation among the claim 1-5 of free form or pharmaceutically acceptable salt form:

The intraocular pressure of glaucoma or rising;

Mental disease, schizophrenia, schizoaffective disorder, schizophreniform disorder, psychotic disease phrenoblabia, delusional disorder and manic are for example in treatment of acute manic episode and bipolar disorder;

Traumatic brain injury.

20. medicine, it comprises any described compound among the claim 1-5 of free form or pharmaceutically acceptable salt form and the pharmaceutically acceptable diluent or carrier of combination or associating with it, is used for the treatment of to be selected from following any disease or illness:

Parkinson's, how moving leg, tremble, movement disorder, Huntington, Alzheimer disease and drug-induced ataxia; Depression, attention deficit disorder, attention-deficit hyperactivity disease, bipolar disorder, anxiety, sleep-disorder, hypnolepsy, Cognitive function damage, dementia, tourette's syndrome, autism, fragile X syndrome, incitantia is given up and/or drug habit; Cranial vascular disease, apoplexy, CHD, hypertension, pulmonary hypertension and/or sex dysfunction; Asthma, COPD and/or allergic rhinitis, and autoimmunity and inflammatory disease; And/or the endometrial hyperplasia or the cancer of female sex dysfunction, exercise related amenorrhea, no ovulation, menopause, menopausal symptom, hypothyroidism, premenstrual syndrome, premature labor, infertile, irregular menstrual cycle, AUB, osteoporosis, multiple sclerosis, prostate increase, prostate cancer, hypothyroidism, oestrogenic hormone-induce; And/or be feature and/or be any disease or the illness of feature with the d1 dopamine receptor signaling activity of reduction with low-level (the perhaps inhibition of cAMP and/or cGMP signal transduction path) of cAMP and/or cGMP in expressing the cell of PDE1; And/or can be by strengthening any disease or the illness that the conduction of progesterone signal is enhanced;

The intraocular pressure of glaucoma or rising;

Mental disease, schizophrenia, schizoaffective disorder, schizophreniform disorder, psychotic disease phrenoblabia, delusional disorder and manic are for example in treatment of acute manic episode and bipolar disorder; With

Traumatic brain injury.